(i) Field of the Invention
This invention relates to a novel composition for use as an insulin mimic comprising peroxide and vanadate. The mimic can produce insulin effects in the absence of insulin.
(ii) Description of the prior art
Since the discovery of insulin there has been a treatment for diabetes mellitus. In about 85% of cases insulin deficiency is not significant; rather there is a resistance in tissues to the effectiveness of the insulin. Oral hypoglycemic agents have been developed, in tablet and capsule form, to treat diabetes mellitus. These agents have been used to replace insulin in the type of disease where there is no severe deficiency of insulin. They act primarily by stimulating increased insulin production from the pancreas, though some appear to influence the peripheral action of insulin.
Insulin acts initially by binding to its receptor site in target tissues. The receptor consists of a portion which binds the insulin molecule and another portion which initiates the biologic response. This latter has been shown to be a protein kinase. Insulin binds to its receptor and activates the protein kinase which then changes the cellular milieu and thus leads to the characteristic responses to insulin.
It is known that vanadate alone is a weak mimicker of insulin action probably through increasing the protein kinase activity, see "Vanadate Augments Adipocyte IGF-2 binding in a manner similar but not identical to insulin" by S. Kadota et al., (abstract presented at the American Diabetes Association Meeting in Anaheim, Calif. on 23rd June 1986). (IGF stands for insulin growth factor). In the same abstract it was disclosed that 1mM H.sub.2 O.sub.2 markedly augmented the effect of vanadate in promoting the translocation of IGF receptors from within the fat cell to the cell surface. This is based on the observation that vanadate +H.sub.2 O.sub.2 (1mM) increased the cell surface binding of .sup.125 I-IGF-2 by 199% over that produced by vanadate alone.
In addition, vanadate has been put in the drinking water of diabetic rats and has been shown to lower blood glucose and to improve cardiac performance in these animals (C.E. Heyliger (1985), Science, Vol. 227: p. 1474-1477). Thus there are data in the literature pointing to applicability of some form of vanadate.
It has now been found that vanadate and peroxide, when mixed together, are potently synergistic in producing an insulin effect. Furthermore, this combination produces an intense stimulation of the receptor's protein kinase. It has recently been found that the combination works because peroxide alters the vanadate to produce a peroxide of vanadate which is many times more potent than the original vanadate and even more potent than maximal doses of insulin in producing an insulin-like effect. The possibility is envisaged that this simple yet very powerful compound has clinical application in the treatment of diabetes mellitus, both the insulin deficient kind and that in which there is tissue resistance to the action of insulin. It represents a new class of agent capable of bypassing the insulin binding site and chemically activating the receptor's protein kinase independently of the ambient levels of insulin. To date there is no known pharmacological agent which can "turn on" the insulin receptor protein kinase to produce insulin effects in the absence of insulin.